New class of ligands for the Parkinson's disease activator protein discovered with participation of Kazan University

Scientists have focused on alpha-synuclein.

Scientists from Kazan Federal University have conducted a study that could potentially impact treatment approaches for severe neurodegenerative diseases. The results were published in ACS Chemical Neuroscience.

The study was supported by the Priority 2030 program as part of the project Molecular Basis of Amyloid Formation and Anti-Amyloid Activity, led by Igor Sedov and colleagues from the Kazan Institute of Biochemistry and Biophysics of the Kazan Scientific Center of the Russian Academy of Sciences and Moscow State University.

The study focuses on alpha-synuclein, a protein that plays a key role in the development of Parkinson's disease. The study demonstrates for the first time that tricyclic antidepressants—drugs long and widely used in medical practice—can directly interact with this protein and slow the formation of dangerous protein aggregates.

In healthy people, alpha-synuclein is essential for neuronal function. However, in Parkinson's disease and some other disorders, it begins to form toxic aggregates—fibrils and Lewy bodies. Blocking this process is one possible strategy for combating the disease. The search for potential drugs is complicated by the very nature of the target protein: alpha-synuclein is a so-called "intrinsically disordered" protein.

"The problem can be defined as the search for new potential ligands for the synuclein protein in the pathogenesis of neurodegenerative diseases, or more broadly, as the search for ligands for intrinsically disordered proteins. The difficulty is primarily due to the fact that disordered proteins lack a rigid spatial structure and classical ligand-binding pockets. Because of this, small organic molecules rarely exhibit high affinity for such proteins, and any substances for which binding can be demonstrated are of interest." Classical methods of computer modeling of protein-ligand interactions also prove inapplicable," comments Dr. Sedov, Lead Research Associate of the Institute of Chemistry of KFU.

During the study, the scientists turned to searching for the activity of already approved drugs. Among the substances studied, tricyclic antidepressants imipramine, amitriptyline, and doxepin demonstrated activity. Experiments using NMR spectroscopy demonstrated that all three drugs indeed bind to alpha-synuclein, preferentially to its C-terminal domain, which is responsible for protein aggregation.

"There's another interesting aspect in our case. Since we were working with clinically approved drugs used to treat other diseases, repurposing the drugs is possible, which is a very interesting strategy, as it eliminates some of the necessary clinical trials," notes Sedov.

A study of the rate of aggregation in the presence of antidepressants confirmed the findings: protein fibrilization was significantly slowed. The strongest binding and most effective inhibition were observed for imipramine.

Molecular dynamics simulations were used to interpret the observed effects at the atomic level. Antidepressant molecules interact with protein amino acid residues in various ways, including electrostatic attraction to negatively charged residues, pi-stacking of aromatic rings, and hydrophobic contacts. In this process, antidepressant molecules can "stick" to the C-terminal fragment, preventing it from binding to other protein molecules and triggering the pathological aggregation process.

The developed computer models can be used for virtual screening of molecules in the search for new treatments for neurodegenerative diseases in the synucleinopathies class.

"Our data also provide new insights into clinical observations made back in 2012. It was noted at the time that taking tricyclic antidepressants in the early stages of Parkinson's disease, compared to other types of antidepressants, delayed the need for specific therapy. However, this had not been explained at the molecular level. Perhaps we have now found an explanation," adds Senior Research Associate, co-author Dilyara Khaibrakhmanova.

More information:
Tricyclic Antidepressants as Prospective α-Synucleinopathy Fighters: Evidence of Protein Binding and Antiaggregation ActivityClick to copy article link
pubs.acs.org/doi/10.1021/acschemneuro.5c00908

Provided by Kazan Federal University